DESCRIPTION (provided by applicant): The introduction of 1-34rhPTH (TPTD) for treatment of individuals with osteoporosis at high risk of fracture changed the paradigm and gave clinicians an agent that has the capacity to correct the underlying architectural defect that is the hallmark of osteoporosis. Our group has a long-standing interest in the effects of TPTD on bone and have an ongoing study designed to look mechanistically at TPTD effects on bone, into which we have recruited 150 women with osteoporosis who were either treatment na¿ve or who had been previously treated with alendronate. These individuals are being followed for 2 yrs (4 three TPTD month cycles or 2 yrs daily treatment). This application is a logical extension of that ongoing study and takes advantage of this unique population of TPTD-treated patients to compare the effects of teriparatide given cyclically (8 three month cycles) over 4 years with teriparatide given daily for 2 years on BMD of the spine and hip by DXA and QCT and BMD and microstructure of the radius and tibia assessed by high resolution pQCT. The specific aims are to determine in treatment na¿ve and alendronate-treated subjects: 1. If TPTD given cyclically (3months on, 3 months off) over a 4 year period produces a clinically meaningful greater increase in BMD by DXA than 2 years of daily TPTD. 2. If QCT (hip, spine, radius and tibia), and FEA modeling of CT data, show enhanced effects of TPTD treatment or simply mirror DXA data. 3. If the tachyphylaxis seen with daily TPTD is caused by depletion of osteoblast precursors, and if it can be obviated by cyclic administration of TPTD. There is no other cohort, and nor will there be, any similar cohort in which these important and clinically relevant aims can be addressed. We believe that our population of subjects treated with TPTD allows us a unique opportunity to determine these clinically important long-term outcomes, since fracture studies with these TPTD regimens are unlikely to be undertaken. The issue of tachyphylaxis to ongoing TPTD administration, will be able to be assessed using the novel technique of an evaluation of the size of the circulating osteoblast pool in cyclic versus daily therapy.

PUBLIC HEALTH RELEVANCE: In this clinical study we will determine the long-term effects of Teriparatide (Forteo or TPTD) on bone structure and strength, in a population of subjects already recruited into a 2 year clinical trial. This study will extend this unique trial by comparing the effects of 2 years of daily TPTD followed by alendronate (Fosamax) with a novel cyclic regimen in which TPTD is given for 3 month intervals followed by 3 month rest periods. The study will also compare the outcomes in women already on alendronate at the start of the protocol and continued on alendronate while being treated cyclically or continuously with TPTD. We will examine whether cyclic treatment can produce repeated stimuli to bone formation over 8 cycles and thus a greater increment in bone strength than 2 years of daily treatment where we know that the effects of TPTD generally decline. We will also test one theory for why this decline occurs, namely that the supply of the bone forming cells (osteoblasts) becomes depleted during the course of the daily regimen. We believe that the periods where no TPTD is given in the cyclic regimen will allow for ongoing recovery of the supply of osteoblasts and will ultimately results in greater gains in bone mass and strength. In this clinical study we will determine the long-term effects of Teriparatide (Forteo or TPTD) on bone structure and strength, in a population of subjects already recruited into a 2 year clinical trial. This study will extend this unique trial by comparing the effects of 2 years of daily TPTD followed by alendronate (Fosamax) with a novel cyclic regimen in which TPTD is given for 3 month intervals followed by 3 month rest periods. The study will also compare the outcomes in women already on alendronate at the start of the protocol and continued on alendronate while being treated cyclically or continuously with TPTD. We will examine whether cyclic treatment can produce repeated stimuli to bone formation over 8 cycles and thus a greater increment in bone strength than 2 years of daily treatment where we know that the effects of TPTD generally decline. We will also test one theory for why this decline occurs, namely that the supply of the bone forming cells (osteoblasts) becomes depleted during the course of the daily regimen. We believe that the periods where no TPTD is given in the cyclic regimen will allow for ongoing recovery of the supply of osteoblasts and will ultimately results in greater gains in bone mass and strength. __SpecificAimsTextDelimiter__ 5.5.2 Specific Aims: This is a resubmission of a proposal to extend for 2 additional years a currently funded study (NIAMS RO- 1AR051454) that evaluates the mechanisms by which teriparatide (TPTD) increases bone mass when given in cyclical fashion or as standard daily therapy in postmenopausal women with osteoporosis who are either treatment na¿ve or alendronate-treated. The original ongoing 2 year study has the following objectives: 1. To explore the mechanism and chronology of different phases of TPTD action using serial biochemical bone turnover markers and histomorphometry at early and later time points using our unique quadruple tetracycline labeling protocol. 2. To compare the bone density (DXA and QCT) and bone turnover response of TPTD given daily with TPTD given cyclically (3 months on and 3 months off) over 2 years with total cumulative TPTD exposure in the cyclic group 50% of that in the daily group. 3. To determine if repeated cycles of TPTD administration can obviate the tachyphylaxis seen over 2 years with daily therapy. This current proposal seeks to extend and expand the original study to obtain long term data on TPTD effects on bone mass, structure and strength when TPTD is given daily or cyclically (3 monthly cycles for 4 years - equivalent cumulative TPTD exposure to 2 years of daily treatment, consistent with Forteo labeling). We also address the question of whether multiple cycles of TPTD treatment can produce repeated stimulation of bone formation over 4 years using both biochemical markers and a novel technique to evaluate the size and maturity of the osteoblast precursor pool. Since daily treatment results in tachyphylaxis during the second year of therapy, our overall hypothesis is that the same cumulative dose of TPTD given in short cycles over 4 years will produce greater effects on bone mass, structure and strength than 2 years of daily treatment. Furthermore, there may be differences in the effects of cyclic TPTD in the presence of alendronate, including a widening of the anabolic window. Finally we will address the issue of tachyphylaxis to ongoing TPTD administration, by assessing the size of the circulating osteoblast pool over the course of 4 years of cyclic therapy as compared to 2 years of daily therapy. There is no other cohort, and nor will there ever be, any similar cohort in which these aims can be addressed. Within this unique cohort, this proposal has the following specific aims: To determine in treatment na¿ve and alendronate-treated subjects: 1. If TPTD given cyclically (3months on, 3 months off) over a 4 year period produces a clinically meaningful greater increase in BMD by DXA than 2 years of daily TPTD. 2. If QCT (hip, spine, radius and tibia), and FEA modeling of CT data, show enhanced effects of TPTD treatment or simply mirror DXA data. 3. If the tachyphylaxis seen with daily TPTD is caused by depletion of osteoblast precursors, and if it can be obviated by cyclic administration of TPTD.